Antibiotics and other chemotherapeutic agents

Antibiotics and other chemotherapeutic agents

The treatment of a disease with a chemical substance is known as chemotherapy; the chemical substance is called a chemotherapeutic agent. Chemotherapy has been practiced for centuries, but it was only early in the present century (the mid-1930s) that this kind of therapy revolutionized the field of medicine. This turn of events is attributed to two discoveries. The first was the finding that sulfonamide compounds (sulfa drugs) could be used successfully for the treatment of certain bacterial diseases. The second was the discovery of a new and potent class of antibacterially active chemotherapeutic agents, namely, antibiotics. In this chapter, we present a brief history of chemotherapy and then discuss the modern chemotherapeutic substances. Emphasis is given to antibiotics and particularly the manner in which they inhibit or kill microbial cells.

Chemotherapeutic agents and chemotherapy

Chemotherapeutic agents are the chemical substance used for the treatment of infectious diseases or diseases caused by the proliferation of malignant cells. These substances are prepared in the chemical laboratory or obtained from microorganisms and some plants and animals. In general, naturally occurring substances are distinguished from synthetic compounds by the name antibiotics. Some antibiotics are prepared synthetically, but most of them are prepared commercially by microbial biosynthesis. Antitoxins and other substances produced by the bodies of infected animals are not considered to be chemotherapeutic agents; the compounds used for killing or inhibiting microbial growth in vitro are not classified as chemotherapeutic agents but usually as disinfectants, antiseptics, or germicides.

To be useful as a chemotherapeutic agent a substance must have selective toxicity for the parasite, which means a low toxicity for host cells and high toxicity for the parasite. In other words, the substance must damage the parasite and cause little or no damage to the cells of the host. For this and other reasons antiseptics and germicides such as phenol, coal-tar derivatives, and many mercurial compounds are unsatisfactory as chemotherapeutic agents. Germicides are not selective in their action on cells, and they interfere with such natural defense mechanisms as phagocytosis; since they do not penetrate cells and tissues well, they do not come into contact with the parasites; because they are inactivated by protein, their effectiveness is destroyed by body fluids rich in protein; and finally, the tissues killed by the germicide or antiseptic provide an excellent medium for microorganisms to grow.

Since the reasons enumerated above make some chemical compounds useless in treating microbial infections, it follows that a satisfactory chemotherapeutic agent must:

1. Destroy or prevent the activity of a parasite without injuring the cells of the host or with only minor injury to its cells
2. Be able to come in contact with the parasite by penetrating the cells and tissues of the host in effective concentrations
3. Leave unaltered the host’s natural defense mechanisms, such as phagocytosis and the production of antibodies

Historical highlights of chemotherapy

Europeans used natural quinine from the bark of the cinchona tree to treat malaria as early as 1630. It was used even earlier by South American Indians, who relieved symptoms of malarial fever by chewing the bark of the cinchona tree.

Ehrlich, Salvarsan, and syphilis

Syphilis is the first known disease for which a chemotherapeutic agent was used. Mercury was used to treating syphilis as early as 1945, but it was not until about 1910 when an arsenical compound known as Salvarsan was synthesized by Paul Ehrlich, that a specific drug capable of curing disease without great danger to the patient was developed. Ehrlich’s contributions were especially important because his was the first systematic and deliberate search for a compound that had potent microbial properties, low toxicity for humans and other animals, and good chemical stability. For this important discovery, he was awarded a share, with Elie Metchnikoff, of the 1908 Nobel prize in physiology and medicine. Ehrlich’s compound has now been replaced in syphilis therapy by arsphenamine, neoarsphenamine, and other arsenical compounds and antibiotics.

Domagk, sulfonamides, and bacterial infections

Because of the effectiveness of Ehrlich’s drug, it is rather surprising that no further significant development in the synthesis of chemotherapeutic agents occurred until 1935 when Domagk showed the therapeutic value of a group of compounds known as the sulfonamides. These substances are not specific for a special group of organisms, as arsphenamine is for Treponema, but are effective against a large variety of pathogenic organisms. Sulfanilamide, the first compound in this group to be synthesized, was made by Gelmo in 1908, and in 1913 Eisenberg studied the bactericidal properties of azo dyes with a sulfonamide grouping. Possibly progress in this field was delayed because of the hesitancy of physicians to accept a type of therapy that Ehrlich referred to as “the chemical knife” since it really amounted to “cutting out” microbes from tissues. Ehrlich was justified in this designation because the use of such drugs was attended by danger to the patient comparable to surgical risk. Fortunately, the new chemotherapeutic agents are not dangerous drugs since they are carefully studied in the laboratory followed by extensive clinical trials. A more realistic explanation for non-acceptance of Ehrlich’s concept of chemotherapy is that it was then generally believed that the struggle between host and parasite was too complex to permit such a direct attack, it would be better, his opponents reasoned, to stimulate the host’s defenses.

After domagk’s reports in 1935 in Germany and confirmatory work by investigators in other countries –notably England, France, and later the united states- interest in chemotherapy reached an all-time high. The compound on which Domagk reported was known as prontosil. French chemists at the Pasteur institute who studied its action on bacteria and attempted to improve it discovered that its bacterial activity is due to the sulfanilamide moiety, previously synthesized and reported by Gelmo in 1908. This observation lighted the fuse for an explosive search for related compounds having therapeutic value. By 1945 it was estimated that several thousand derivatives of sulfanilamide had been made.

The important result of the search for new varieties of sulfonamides has been the development of drugs with increased antibacterial activities and fewer unfavorable reactions in the host animal. Some have been especially useful in certain types of infections, but sulfadiazine and sulfamerazine are extensively used because of their antibacterial effectiveness in a wide range of bacterial infections and because they are least likely to produce toxic reactions in the patient.

The sulfonamides are especially useful in the treatment of infections caused by meningococci and Shigella, respiratory infections caused by Streptococci and Staphylococci, and urinary infections due to gram-negative organisms. They are useful in the prevention of rheumatic fever, bacterial endocarditis, would infections, and urinary tract infections following surgery or catheterization.

References

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